Narcolepsy is a disabling neurological disorder affecting more than 1 in 2,00 Americans. This program project is the only existing NIH funded multi-disciplinary program focusing on this disorder. Our previous funding has led to significant advances such as the identification and genetic characterization of canine narcolepsy [the only known animal model for this condition], the dissection of the mode of action of currently prescribed narcolepsy treatments and the discovery that HLA- DBQ1*0602, rather than the previously identified HLA-DR2 antigen, is a genuine human narcolepsy susceptibility gene. A neuroanatomical map of the structures and neurotransmitters involved in the pathophysiology of narcolepsy is also being established. A solid linkage marker for the canine narcolepsy gene, canarc-1 was also identified and the genomic segment containing the deficient gene was flanked and physically cloned using a Bacterial Artificial Chromosome (BAC) genomic library build specifically for this purpose. In the next funding period, a new project, Project B, will be initiated in Wisconsin Sleep Cohort. The goal of this project is to define the spectrum of narcolepsy and its symptoms in the general population using HLA typing in the context of an epidemiological approach. Once completed, this project will have direct clinical applications. It will provide the scientific community with the first prevalence estimate for narcolepsy without cataplexy. It will help clinicians and researchers to better define and thus treat this disorder at a time when new stimulant treatments are being increasingly used (and perhaps misused) for the treatment of narcolepsy. The second and third projects are direct continuations of our previous efforts. Project D will further characterize the neuroanatomical and neurophysiological approach. Project C will complete the cloning of canarc-1 and study the function of this deficient gene. Based on the rapid pace of our previous progress, we are confident that we will identify canarc-1 during the next funding period. Whether or not this gene is involved in human narcolepsy, the identification of canarc-1 will be a landmark in our understanding of narcolepsy and sleep control.